For a great many years, therapy for those individuals suffering from diabetes mellitus has involved the periodic injection of aqueous and/or saline solutions of the protein hormone, insulin. Injections of insulin are necessary to effectuate metabolism of carbohydrates lipids and amino acids in the afflicted individual who does not possess the ability to internally synthesize this vital hormone. It will be appreciated that the injection technique of therapy results in the introduction of large quantities of insulin into the individual on a periodic basis. These periodic doses and subsequent availability in the metabolic process may not necessarially coincide with high carbohydrate, lipid and amino acid levels in the blood stream of the afflicted individual. Therefore, despite the effectiveness of the insulin injections there is still considerable possibility of a "mismatch" between the levels of carbohydrate, lipids, and amino acids in the individual's blood stream and the concurrent availability of insulin to mediate their metabolism.
In recent years techniques have been developed for preparing "extended" suspensions of insulin which, upon injection, release the hormone more slowly into the blood stream. However, even these techniques result in changes in insulin levels in the blood, which levels do not necessarily coincide with the insulin demand for metabolism.
In order to provide the insulin levels metabolically required over extended periods of time, resort has been made to the development of continual or regulated feed directly or indirectly devices which may be permanently attached, either externally or internally, to the body of the individual. Such devices include a reservoir of insulin solution which is fed on a continuing or controlled basis into the blood stream of the individual. Such devices require the reservoir of insulin solution as a source for the introduction of the hormone into the individual.
Although such devices show great promise in overcoming the difficulties referred to above, an unexpected defect has now appeared which threatens the viability, efficiency and acceptability of such devices. Specifically, when insulin solutions are maintained at or about body temperatures e.g. 37.degree. C., and are subjected to agitation by the individual's movements, self aggregation of the insulin occurrs. Aggregation results in the precipitation of insulin complexes from the solution. Such a phenomenon occurs within a relatively short period of time i.e., in the matter of hours to several days under the conditions noted. This precipitation may occur within the insulin reservoir itself and even more importantly, within the catheters utilized to deliver the insulin solution into the blood stream of the individual. It will be readily apparent that such catheters are, of necessity, very small in size and in essence, comprise capillary passages from the reservoir into the tissues of the individual. The aggregation of the insulin therefore tends to collect within the catheter passages and results in their occlusion. The insulin flow is thereby diminished or even stopped. Even if flow continues, the aggregates can be biologically inactive.
A number of investigators have addressed this insulin aggregation problem. Perhaps the best review of the state of the art is the article by Lougheed et. al. published in Diabetologia, 19, pages 1-9 (1980) and entitled "Insulin Aggregation in Artificial Delivery Systems". This article reviews all of the relevant literature to date, discusses the various factors considered to affect the aggegation of insulin solutions; reviews the results of several experiments; and attempts to stabilize insulin solution by the addition of a rather broad spectrum of supplemental materials such as ethylene diamine tetraacetic acid (EDTA) sodium bicarbonate, sodium chloride, cysteine, benzol alcohol, hydrochloric acid, histidine, sodium phosphate, glycine, etc. All such materials, however, do not appear to have any appreciable effect in preventing the aggregation of insulin in solution over extended periods of time. Albisser et. al. in Diabetes, 29, pages 241-243 (1980) have reported that the addition of serum to insulin solutions promotes solubilization. However, the problems of supply, purification, and potential protein reaction would indicate that such an approach is not entirely practical at this time.
Thus, up to the present time, the problem of the aggregation of insulin in solutions maintained at body temperature, and under conditions of agitation, seriously threatens the viability of artificial pancreatic devices intended to operate over time periods exceeding several days.